Somatostatin was isolated from ovine hypothalamus and identified as a growth hormone inhibiting factor (Guillemin, R. et al., Science, vol. 179, pp. 77–79, 1973). Somatostatin is composed of 14 amino acid residues and has a cyclic structure resulting from the S—S bond between Cys in position 3 and Cys in position 14 (somatostatin-14). Somatostatin-28, which is composed of somatostatin-14 and 14 amino acid residues added to the N-terminus of the somatostatin-14 molecule, has also been identified.
Somatostatin is broadly distributed in the central nervous system and, peripherally, occurs in such organs as the spleen and gastrointestinal tract, and further in the peripheral nerves. It is now known that this substance inhibits not only secretion of growth hormone but also secretion of pituitary hormones such as thyroid-stimulating hormone and prolactin and digestive tract hormones such as gastrin and insulin and that it also acts as a neurotransmitter (Brownstain, M. et al., Endocrinology, vol. 96, pp. 1456–1461, 1975). Furthermore, it has been found to inhibit cell proliferation. Therefore, various derivatives of somatostatin have been synthesized and tried for clinical application for the purpose of inhibiting hormone hypersecretion or tumor growth.
A novel neuropeptide similar in structure to somatostatin has been reported by a team of researchers at Scrips Laboratories. It has been revealed that this peptide named rat cortistatin (the precursor thereof being referred to as preprocortistatin) is the product of a gene different from the somatostatin gene. However, cortistatin has the property to selectively shorten the REM (rapid eye movement) sleep phase during sleep and generate low-frequency waves in the cerebral cortex. Further, cortistatin impedes the effects of acetylcholine, which is itself a REM sleep inducer. It is supposed that cortistatin acts as a modulator of neural activities and sleep (L. de Lecea et al., Nature, 381, 16 May 1996).
The activities of somatostatin depend on its binding to the specific high-affinity receptors (somatostatin receptors) present on the cell membrane and the consequent transduction of its signal through the GTP-binding protein to the intracellular signal transduction system. First, the structure of somatostatin receptor subtype 1 (hereinafter sometimes referred to as SSTR1) and that of subtype 2 (hereinafter sometimes referred to as SSTR2) were determined and reported (Yamada et al., Proc. Natl. Acad. Sci. USA, vol. 89, pp. 251–255, 1992). Then, DNAs coding for subtype 3 (hereinafter sometimes referred to as SSTR3), subtype 4 (hereinafter sometimes referred to as SSTR4) and subtype 5 (hereinafter sometimes referred to as SSTR5), respectively, were cloned (SSTR3: Yamada et al., Molecular Endocrinology, vol. 6, pp. 2136–2142, 1992; SSTR4 and SSTR5: Yamada et al., Biochem. Biophys. Res. Commun., vol. 195, pp. 844–852, 1993). These so-far known five somatostatin receptor subtypes are 42–60% homologous with one another on the amino acid level.
The activities of cortistatin are also supposedly displayed upon its binding to the specific high-affinity receptors on the cell membrane and the consequent transduction of its signal through the GTP-binding protein to the intracellular signal transduction system. In fact, cortistatin-14 undergoes a displacement similar to that of somatostatin in response to the binding of [125I]-labeled somatostatin on the membrane of the rat pituitary cell GH4 (L. de Lecea et al., Nature, 381, 16 May 1996). However, a possible difference in effect, for example on sleep, has been suggested between somatostatin-14 and cortistatin-14 intraventricularly administered to rats, and differences in affinity and site of action have been implied between the respective peptides with respect to somatostatin receptor subtypes and somatostatin receptor-like receptors. Furthermore, the probability has been pointed out that cortistatin also acts on receptors other than somatostatin receptors. For instance, GPR7 (U22491) and GPR8 (U22492) are reported to be receptors with high homology to somatostatin receptors although the binding thereof to somatostatin has not been established as yet [Genomics, 28, 84–91, (1995)]. It is considered possible that cortistatin act on such receptors as well. As mentioned above, cortistatin supposedly plays important roles in the regulation of physiological functions in vivo via specific receptors but no human-related somatostatin-like or cortistatin-like peptides are known as yet.
Attempts have been reportedly made to determine gene expression levels or discover novel genes in organs and cells by determining partial sequences (expressed sequence tags; abbreviated as ESTs) of cDNA clones randomly selected from among cDNA libraries. M. D. Adams et al. have reported a number of ESTs obtained from a brain cDNA library (Nature Genetics, vol. 4, pp. 373–380, 1993).
The novel physiologically active peptides having somatostatin-like or cortistatin-like activity are expected to enable development of novel drugs of value in the prevention or treatment of acute bacterial meningitis, acute myocardial infarction, acute pancreatitis, acute viral encephalitis, adult respiratory distress syndrome, alcoholic hepatitis, Alzheimer's disease, asthma, arteriosclerosis, atopic dermatitis, bacterial pneumonia, bladder cancer, bone fracture, mammary cancer, hyperphagia, polyphagia, burn healing, carcinoma of the uterine cervix, chronic lymphatic leukemia, chronic myelocytic leukemia, chronic pancreatitis, hepatic cirrhosis, colorectal cancer (carcinoma of the colon/rectum), Crohn's disease, dementia, diabetic complications, e.g. diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc., gastritis, Helicobacter pylori infection, hepatic insufficiency, hepatitis A, hepatitis B, hepatitis C, other types of hepatitis, herpes simplex virus infection, varicella-zoster virus infection, Hodgkin's disease, AIDS virus infection, human papilloma virus infection, hypercalcemia, hypercholesterolemia, hyperglyceridemia, hyperlipemia, miscellaneous infectious diseases, influenza virus infection, insulin-dependent diabetes melitus (type I), invasive staphylococcal infection, malignant melanoma, cancer metastasis, multiple myeloma, allergic rhinitis, nephritis, non-Hodgkin's lymphoma, noninsulin-dependent diabetes melitus (type II), non-small-cell lung cancer, organ transplantation, osteoarthritis, osteomalacia, osteopenia, osteoporosis, ovarian cancer, osteo-Behcet's disease, peptic ulcer, peripheral vascular disease, prostatic cancer, reflux esophagitis, renal failure, rheumatoid arthritis, schizophrenia, sepsis, septic shock, severe systemic fungal infection, small-cell lung cancer, spinal injury, stomach cancer, systemic lupus erythematosus, transient cerebral ischemic attack, pulmonary tuberculosis, valvular heart disease, vascular/multiple infarction-associated dementia, wound healing, insomnia, arthritis, and neurodegenerative disease, among other diseases.